Ionizing radiation (IR) exposure has been associated with increased rate of cancer incidence for over 100 years, but the mechanism underlying this relationship remains poorly understood. IR-induced cancers include lung, skin, thyroid, breast, stomach cancers, and most commonly, leukemias. Long-term studies following humans exposed to large doses of radiation indicate decreased cellular function up to 50 years after the initial exposure, most notably in the hematopoietic compartment. IR-induced carcinogenesis is conventionally attributed to the direct generation of oncogenic mutations. However, our lab has developed an evolutionary based model for cancer development, Adaptive Oncogenesis. Essentially, young, healthy cells maintain high tissue fitness and prevent expansion of oncogenically-initiated cells by outcompeting damaged and mutant cells for nutrients and room. Damage to the entire cellular population, such as after total-body irradiation, decreases the fitness of the population, thereby increasing selective pressure for adaptive oncogenic mutations. Competitive bone marrow transplants, along with ex vivo HSC cultures, indicate that IR exposure causes stable defects in HSC maintenance that can be reversed by activation of Notch1 signaling. The goal of this research proposal is two-fold. 1. To identify the mechanism by which previous IR decreases HSC maintenance; 2. To explore how impaired HSC fitness impacts selection for adaptive oncogenes and leukemogenesis. The research proposal emphasizes a basic biological understanding of hematopoietic fitness maintenance and the foundations of IR-induced carcinogenesis, with potential implications in cancer prevention. The proposed research will help the National Cancer Institute fulfill their mission to support cancer research and training in the fundamental sciences. PUBLIC HEALTH RELEVANCE: Exposure to radiation has long been linked to an increased risk of cancer, though the underlying mechanism(s) remains to be determined. This proposal will attempt to characterize the mechanism(s) whereby long-term radiation induces defects of the hematopoietic stem cell population and mechanisms by which cancer-causing genes reverse or circumvent these defects, thereby promoting cancer development. Understanding the foundations of IR-induced cancer and the importance of normal stem cell function in tumor suppression will be critical for development of cancer prevention and treatment strategies.